Potassium secretion by the descending limb or pars recta of the juxtamedullary nephron in vivo

Potassium secretion by the descending limb or pars recta of the juxtamedullary nephron in vivo. Potassium reabsorption by the juxtamedullary nephron up to the hairpin turn was studied by the micropuncture technique in the exposed renal papilla of rats. In 18 nondiuretic rats, the fraction of filtered potassium remaining at the end of the desdending limb averaged 113 ± 9%, indicating either that potassium is not reabsorbed by the juxtamedullary proximal tubule and descending limb or that potassium is reabsorbed and secreted in those segments. Furosemide, a drug which inhibits NaCl reabsorption in the ascending limb downstream from the descending limb, significantly decreased the potassium remaining at the end of the descending limb from 106 ± 12 to 72 ± 11% in seven rats. Benzolamide, a drug which inhibits reabsorption of NaHCO3 and water in the proximal tubule upstream from the descending limb, significantly increased the potassium remaining from 103 ± 13 to 177 ± 32% in eight rats. These findings support the hypothesis that in the rat, potassium is normally reabsorbed by the proximal convoluted tubule and secreted in the pars recta or descending limb of the juxtamedullary nephron

Epigenetic age acceleration in adolescence associates with BMI, inflammation and risk score for middle age cardiovascular disease

BACKGROUND: 'Accelerated ageing', assessed by adult DNA methylation predicts cardiovascular disease (CVD). Adolescent accelerated aging might predict CVD earlier. We investigated whether epigenetic age acceleration (assessed age 17-years) associated with adiposity/CVD-risk measured (ages 17, 20, 22-years), and projected CVD by middle-age. METHODS: DNA methylation measured in peripheral blood provided 2 estimates of epigenetic age acceleration; intrinsic (IEAA, (preserved across cell types) and extrinsic (EEAA, dependent on cell admixture and methylation levels within each cell type).Adiposity was assessed by anthropometry, ultrasound and DEXA (ages 17, 20, 22 years). CVD-risk factors (lipids, HOMA-IR, blood pressure, inflammatory markers) were assessed at age 17-years. CVD development by age 47 years was calculated by Framingham algorithms. Results are presented as regression coefficients/5-year epigenetic age acceleration (IEAA/EEAA) for adiposity, CVD-risk factors and CVD development. RESULTS: In 995 participants (49.6% female, age 17.3+/-0.6 years), EEAA (/5-years) was associated with increased BMI of 2.4% (95%CI 1.2-3.6%) and 2.4% (0.8-3.9%) at 17 and 22 years, respectively. EEAA was associated with increases of 23% (3-33%) in hsCRP, 10% (4-17%) in interferon-gamma induced protein (IP-10) and 4% (2-6%) in tumour necrosis factor receptor 2 (sTNFR2), adjusted for BMI and HOMA-IR. EEAA(/5-years) results in a 4% increase in hard endpoints of CVD by 47 years old and a 3% increase, after adjustment for conventional risk factors. CONCLUSIONS: Accelerated epigenetic age in adolescence was associated with inflammation, BMI measured 5 years later, and probability of middle-age CVD. Irrespective whether this is cause or effect, assessing epigenetic age might refine disease prediction

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass

Left ventricular mass (LVM) and cardiac gene expression are complex traits regulated by factors both intrinsic and extrinsic to the heart. To dissect the major determinants of LVM, we combined expression quantitative trait locus1 and quantitative trait transcript (QTT) analyses of the cardiac transcriptome in the rat. Using these methods and in vitro functional assays, we identified osteoglycin (Ogn) as a major candidate regulator of rat LVM, with increased Ogn protein expression associated with elevated LVM. We also applied genome-wide QTT analysis to the human heart and observed that, out of 22,000 transcripts, OGN transcript abundance had the highest correlation with LVM. We further confirmed a role for Ogn in the in vivo regulation of LVM in Ogn knockout mice. Taken together, these data implicate Ogn as a key regulator of LVM in rats, mice and humans, and suggest that Ogn modifies the hypertrophic response to extrinsic factors such as hypertension and aortic stenosi

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Protein ubiquitination is a dynamic and reversibleprocess of adding single ubiquitin molecules orvarious ubiquitin chains to target proteins. Here,using multidimensional omic data of 9,125 tumorsamples across 33 cancer types from The CancerGenome Atlas, we perform comprehensive molecu-lar characterization of 929 ubiquitin-related genesand 95 deubiquitinase genes. Among them, we sys-tematically identify top somatic driver candidates,including mutatedFBXW7with cancer-type-specificpatterns and amplifiedMDM2showing a mutuallyexclusive pattern withBRAFmutations. Ubiquitinpathway genes tend to be upregulated in cancermediated by diverse mechanisms. By integratingpan-cancer multiomic data, we identify a group oftumor samples that exhibit worse prognosis. Thesesamples are consistently associated with the upre-gulation of cell-cycle and DNA repair pathways, char-acterized by mutatedTP53,MYC/TERTamplifica-tion, andAPC/PTENdeletion. Our analysishighlights the importance of the ubiquitin pathwayin cancer development and lays a foundation fordeveloping relevant therapeutic strategies